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Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21

Nature Immunology volume 6, pages 680–688 (2005)Cite this article

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Abstract

Notch receptors are processed by γ-secretase acting in synergy with T cell receptor signaling to sustain peripheral T cell activation. Activated CD4+ T cells differentiate into T helper type 1 (TH1) or TH2 subsets. Molecular cues directing TH1 differentiation include expression of the TH1-specific transcription factor T-bet, encoded by Tbx21. However, the regulation of Tbx21 remains incompletely defined. Here we report that Notch1 can directly regulate Tbx21 through complexes formed on the Tbx21 promoter. In vitro, γ-secretase inhibitors extinguished expression of Notch, interferon-γ and Tbx21 in TH1-polarized CD4+ cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of γ-secretase inhibitors substantially impeded TH1-mediated disease progression in the mouse experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, using γ-secretase inhibitors to modulate Notch signaling may prove beneficial in treating TH1-mediated autoimmunity.

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Figure 1: Blocking Notch signaling decreases the capacity of CD4+ T cells to adopt a TH1 cell fate without affecting proliferation.
Figure 2: Preventing Notch activation early during polarization abrogates IFN-γ production and expression of Notch1 and phospho-STAT4.
Figure 3: Tbx21 mRNA expression is abrogated by 48 h in the absence of Notch signaling and Tbx21 mRNA is re-expressed after expression of activated Notch1.
Figure 4: CSL binds constitutively to putative consensus sites in the Tbx21 promoter and forms a complex with activated Notch1.
Figure 5: GSI treatment ameliorates symptoms of EAE and inhibits in vivo biological responses.

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  • 06 July 2018

    This article was initially published with an incorrect DOI. A new DOI has been assigned and registered at Crossref, and has been corrected in the article.

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Acknowledgements

The authors thank members of the Osborne Lab for discussions and R.A. Goldsby for critical reading of the manuscript. Supported by a Ruth L. Kirschstein National Research Service Award (L.M.M.).

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Author notes

  1. Lisa M Minter and Danielle M Turley: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, 01003, Massachusetts, USA

    Lisa M Minter, Hyun Mu Shin, Ila Joshi, Rebecca G Lawlor, Ok Hyun Cho, Sridevi Gottipati, Janice C Telfer, Kimberly A Such & Barbara A Osborne

  2. Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA

    Danielle M Turley & Stephen D Miller

  3. Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, 32224, Florida, USA

    Pritam Das, Lisa Kostura, Abdul H Fauq, Katherine Simpson & Todd E Golde

  4. Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand

    Tanapat Palaga

  5. Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, 60612, Illinois, USA

    Lucio Miele

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Supplementary information

Supplementary Fig. 1

GSI abrogates IFN-γ secretion but CD44 expression and its affinity for ligand is unaffected.

Supplementary Fig. 2

Retroviral infection efficiencies of CD4+ T cells are comparable in DMSO- and GSI-pretreated cells, regardless of polarizing conditions.

Supplementary Fig. 3

Putative CSL binding sites are located in the murine Tbx21 promoter region.

Supplementary Fig. 4

Oral GSI treatment during EAE induction with PLP139-151 decreases ex vivo proliferation and IFN-γ production upon restimulation with peptide.

Supplementary Methods

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Minter, L., Turley, D., Das, P. et al. Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat Immunol 6, 680–688 (2005). https://doi.org/10.1038/ni1209x

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